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Novel highly potent CD4bs bNAb with restricted pathway to HIV-1 escape

Schommers, P. and Gruell, H. and Abernathy, M. E. and Dingens, A. S. and Tran, M.-K. and Gristick, H. B. and Barnes, C. O. and Schoofs, T. and Schlotz, M. and Vanshylla, K. and Kreer, C. and Weiland, D. and Holtick, U. and Scheid, C. and Valter, M. M. and van Gils, M. J. and Sanders, R. W. and Vehreschild, J. J. and Cornely, O. A. and Lehmann, C. and Fätkenheuer, G. and Seaman, M. S. and Bloom, J. D. and Bjorkman, P. J. and Klein, F. (2019) Novel highly potent CD4bs bNAb with restricted pathway to HIV-1 escape. HIV Medicine, 20 (S9). p. 50. ISSN 1464-2662.

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Purpose: Broadly HIV-1 neutralizing antibodies (bNAbs) can suppress viremia in humans and represent a novel approach for effective immunotherapy. However, bNAb monotherapy selects for antibody-resistant viral variants. Thus, we focused on the identification of new antibody combinations and/or novel bNAbs that restrict pathways of HIV-1 escape. Methods: We screened HIV-1 positive patients for their neutralizing capacities. Following, we performed single cell sorting and PCR of HIV-1 Env-reactive mature B cells of identified elite neutralizers. Found antibodies were tested for neutralization and binding capacities in vitro. Further, their antiviral activity was tested in an HIV-1 infected humanized mouse model. Results: Here we report the isolation of antibody 1–18, a VH1–46-encoded CD4 binding site (CD4bs) bNAb identified in an individual ranking among the top 1% neutralizers of 2,274 HIV-1-infected subjects. Tested on a 119-virus panel, 1–18 showed to be exceptionally broad and potent with a coverage of 97% and a mean IC50 of 0.048 lg/mL, exceeding the activity of most potent CD4bs bNAbs described to-date. A 2.4 Å cryo-EM structure of 1–18 bound to a native-like Env trimer revealed that it interacts with HIV-1 env similar to other CD4bs bNAbs, but includes additional contacts to the V3 loop of the adjacent protomer. Notably, in vitro, 1–18 maintained activity against viruses carrying mutations associated with escape from VRC01-class bNAbs. Further, its HIV-1 env wide escape profile differed critically from other CD4bs bNAbs. In humanized mice, monotherapy with 1–18 was sufficient to prevent the development of viral escape variants that rapidly emerged during treatment with other CD4bs bNAbs. Finally, 1–18 overcame classical HIV-1 mutations that are driven by VRC01-like bNAbs in vivo. Conclusion: 1–18 is a highly potent and broad bNAb that restricts escape and overcomes frequent CD4bs escape pathways, providing new options for bNAb combinations to prevent and treat HIV-1 infection.

Item Type:Article
Related URLs:
URLURL TypeDescription
Gristick, H. B.0000-0002-1957-2821
Barnes, C. O.0000-0003-2754-5951
Bloom, J. D.0000-0003-1267-3408
Bjorkman, P. J.0000-0002-2277-3990
Additional Information:© 2019 The Authors. HIV Medicine © 2019 British HIV Association. First published: 06 November 2019.
Issue or Number:S9
Record Number:CaltechAUTHORS:20191121-073720987
Persistent URL:
Official Citation:(2019), EACS 2019 – Abstract Book. HIV Med, 20: 3-316. doi:10.1111/hiv.12814
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:99971
Deposited By: Tony Diaz
Deposited On:21 Nov 2019 17:44
Last Modified:03 Aug 2020 22:15

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